Adamantyl carbazates



United States Patent 3,369,041 ADAMANTYL CARBAZATES Koert Gerzon andEriks V. Krumkalns, Indianapolis, Ind., assignors to Eli Lilly andCompany, Indianapolis, Ind., a corporation of Delaware No Drawing.Original application Jan. 21, 1965, Ser. No. 427,124. Divided and thisapplication Feb. 13, 1967, Ser. No. 615,356

4 Claims. (Cl. 260-482) ABSTRACT OF THE DISCLOSURE Adamantyl carbazates,useful as intermediates, are prepared by reacting hydrazine with threeditferent types of adamantyloxy intermediates.

CROSS-REFERENCE This application is a division of our earlierapplication, Ser. No. 427,124, filed Jan. 21, 1965.

BACKGROUND OF THE INVENTION Adamantane was first isolated from petroleumby Landa and Machacek in 1933 [S. Landa and V. Machacek, Coll. Czech.Chem. Comm., 5, 1 (1933)]. Adamantane and alkylated adamantanes are nowprepared by various synthetic procedures as outlined in Chem. Reviews,64, 277 (1964). The above article also discusses the preparation ofderivatives of adamantane; for example, adamantoic acid, adamantylamine,adamantyl chloride and adamantyl alcohol. Various esters and amides ofadamantoic acid as well as adamantoyl chloride are also described, butonly a few derivatives of adamantyl alcohol.

SUMMARY OF THE INVENTION The compounds provided by this invention can berepresented by the following formulas:

wherein AD is a member of the group consisting of adamantyl,methyladamantyl, dimethyladamantyl and homo-adamantyl; R is a member ofthe .group consisting of hydrogen, C -C alkyl, hydroxy-substituted C -Calkyl, carboxy lower alkyl-substituted C -C alkyl, mercapto-substitutedC -C alkyl, lower alkyl-mercapto-substituted C -C alkyl,guanidino-substituted C -C alkyl, benzyl, substituted benzyl,imidazolylmethyl, indolylrnethyl, hydroxyindolylmethyl, phenyl,substituted phenyl, thienyl, and turyl; R is a member of the groupconsisting of hydrogen and C -C alkyl; and R" is a member of the groupconsisting of hydrogen and hydroxyl. Also included within the scope ofthis invention are alkali metal and amine salts of acids represented bythe above formulas.

Adamantane and homo-adamantane, from which are derived the adamantyl,methyladamantyl, dimethyladamantyl and homo-adamantyl radicals referredto above, are tricyclic multi-bridged hydrocarbons. Their structures areconventionally represented in two dimensions by the following formulas:

. homo-adamantane adamantaue As can be seen from the above formulas, inadaman tane, all oddand all even-numbered positions are equivalent.Homo-adamantane has two pairs of equivalent bridgehead carbon atoms, Cand C and C and C In the above formula, when R or R is C C alkyl, it canbe, illustratively, isobutyl, sec. butyl, isopropyl, npropyl, methyl,ethyl, n butyl and t butyl. When R is a substituted C C alkyl group,said substituents being mercapto, lower alkyl mercapto, carboxy loweralkyl, guanidino, and hydroxy, illustrative radicals which R vcanrepresent include hydroxymethyl, mercaptomethyl, methylmercaptomethyl,methylmercaptoethyl, ethylmercaptomethyl, 7 guanidinobutyl, ,6hydroxyethyl, ,8 hydroxyt butyl, [3 isopropylmercaptoethyl, 'yhydroxypropyl, 'y mercapto n butyl, carboxymethyl, B carboxyethyl, andthe like. The term lower alkyl as used herein means an alkyl grouphaving from 1 to 3 carbon atoms, and includes methyl, ethyl, n propyland isopropyl. When R represents a substituted-benzyl group orsubstituted-phenyl group, the substituents in the phenyl ring can behalo such as fiuoro, chloro, bromo, iodo and the like; lower alkyl,lower alkoxy, hydroxy, and halo-substituted lower alkyl. Thus, groupswhich illustrate R when it is a substituted-benzyl or substituted-phenylradical include 3,5 di iodo 4 hydroxybenzyl, 3,4 dihydroxybenzyl, 4hydroxybenzyl, 4 trifluoromethylbenzyl, 4 trichloromethylbenzyl, 4pentafluoroethylbenzyl, 4 a bromopropylbenzyl, veratryl, isovanillyl,vanillyl, 4 isopropoxybenzyl, 2,4 dimethylbenzyl, 3- isopropylbenzyl, 4chlorophenyl, 2,6 dibromophenyl, m tolyl, 3,4 Xylyl, p anisyl', ppropoxyphenyl, methoxyphenyl, 4 iodophenyl, 3,5 di iodo 4 hydroxyphenyl,p trifluorornethylphenyl, and the like. Other substituents, in additionto those enumerated above, can be present in the phenyl group or in thephenyl portion of the benzyl group Without any qualitative change in theproperties of the parent compound, as will be apparent to those skilledin the art. When R is a hydroxy-substituted indolylmethyl radical, thehydroxy group is in the benzo portion of the indolyl radical. R can thenalso be, illustratively, 5 hydroxyindolymethyl, 6 hydroxyindolylmethyl,and the like.

Illustrative compounds coming Within the scope of this invention includethe following: N-l-adamantyloxycarbonyl L-tyrosineN-3-methyladamantyloxycarbonyl L-phenylalanineN,N-bis-(l-adamantyloxycarbonyl) L-cystineN-3,S-dimethyladamantyloxycarbonyl D-valine Ethyl N3-homo-adamantyloxycarbonyl 2,4-

oxycarbonyl group can act as a blocking group by preventing both thereaction of the blocked amino group with an acylating agent and theformation of a zwitterion. When employed as a blocking group in peptidesynthesis, the adamantyloxycarbonyl group has the advantage of yieldingmore stable derivatives than are obtained with conventional blockinggroups, yet which are at the same time readily hydrolyizable underconditions ordinarily used to remove the conventional blocking groups.In addition, the N adamantyloxycarbonyl derivatives of amino acids, asrepresented by the above formulas, can be used in the synthesis ofpenicillins and cephalosporins. In such reactions, theadamantyloxycarbonyl group again functions as a blocking group,preventing not only reaction of the amino function with cephalosporanicacid or penicillanic acid or with itself, but also formation of anunreactive zwitterion. The ease of splitting the adamantyloxycarbonylgroup from the resulting penicillin or cephalosporin prevents any unduedestruction of the pencillin or cephalosporin necessitated by the use ofmore acidic hydrolytic reagents.

In addition to their ease of hydrolysis, the adamantyloxycarbonylderivatives of amino acids are more easily isolated than thecorresponding compounds using more conventional blocking groups.Furthermore, the adamantylcarbamates themselves are frequentlycrystalline, in contrast to derivatives of amino acids with the moreconventional blocking agents.

The adamantyloxycarbonyl blocking group can be readily cleaved from theadamantylcarbamate by treatment with trifluoroacetic acid or withanhydrous hydrogen chloride in an inert solvent such as dioxane. Othermethods of cleaving these carbamates will readily suggest themselves tothose skilled in the art.

Compounds represented by the above formulas are prepared according tothe following reaction sequence:

Reaction Sequence 1 pyridine A D-O- O=GOAD wherein AD, R, R and R" havethe same meaning as hereinabove. In carrying out the above reactionsequence, l-hydroxyadamantane or 3-methyl-1-hydroxyadamantane or3,S-dimethyl-l-hydroxyadamantane or 3- hydroxyhomo-adamantane is reactedwith phosgene in the presence of a tertiary amine such as pyridine,trimethylpyridine, quinoline, or tri-ethylamine in an inert solvent,such as anhydrous benzene or ether or other hydrocarbon or etherealsolvents, to form the corresponding adamantyl chloroformate. It wascompletely unexpected that the chloroformates of adamantane and itscongeners would be stable inasmuch as t-butylchloroformate, theopen-chain analog of these compounds, is completely unstable and cannotbe isolated, according to Choppin and Rogers, J. Am. Chem. Soc., 70,2967 (1948). The instability of t-butylchloroformate was to be expectedfrom its presumed readiness to form the transient t-butylcarbonium ionwhich disappears rapidly in solution to yield either the correspondingalcohol or chloride or to yield isobutene, depending upon the physicaland chemical environment. No theoretical reason is knOWn why theadamantyl chloroformates do not also spontaneously decompose to yieldthe corresponding carbonium ions and then disappear as the hydroxycompound or the chloride or as tar (inasmuch as an unsaturated compoundcorresponding to isobutene cannot be formed from the 1-adamantylcarbonium ion). Not only are these adamantyl chloroformatessulficiently stable to enable the compound to be used in furtherreactions such as the formation of adamantyloxycarbonyl derivatives, butalso, in the case of l-adamantyl chloroformate itself, for example, thecompound can be isolated as a white crystalline solid with a meltingpoint well above ordinary room temperature.

Inasmuch as the adamantyl chloroformates are reasonably stable at 0 C.,the second step of the reaction, the formation of theN-adamantyloxycarbonyl derivative of the amino acid, takes place readilyand in good yield by simply mixing the two reactants in an inertsolvent, under slightly alkaline conditions. In order to have suchalkaline conditions, we prefer to employ the sodium salt of the aminoacid as the starting material and to add dilute sodium hydroxide or itsequivalent as required in dropwise fashion during the course of thereaction. Useful inert solvents include ethers, such as dioxane orether, alcohols, such as t-butanol or ethanol, and mixtures of thesesolvents with water.

An alternative and somewhat more complex route starting with adamantylchloroformate is available for the preparation of the compounds of thisinvention and is outlined in Reaction Sequence II below.

Reaction Sequence II wherein AD, R, R and R" have the same meaning ashereinabove. According to the above reaction sequence, an N-adamantylchloroformate is reacted with hydrazine to yield the correspondingl-adamantyl or 3-methyl-ladamantyl or 3,5-dimethyl-1-adamantyl or3-hornoadamantyl carbazate. Reaction of the carbazate with nitrous acidyields the corresponding azidoformate, which compound reacts with thea-amino acid to yield an N- adamantyloxycarbonyl derivative of the aminoacid in good yield. The adamantyl carbazates,

AD0ii-NHNH can also be prepared by reacting an adamantyl-p-nitrophenylcarbonate with anhydrous hydrazine or by reacting anO-I-adamantyl-S'met-hyI thiolcarbonate with anhydrous hydrazine.

Although, as indicated above, an adamantyl azidoformate can react withthe amino acid to yield the same derivative as would be obtained byreaction of the amino acid with an adamantyl chloroformate, there is aconsiderable advantage to using the chloroformate in place of theazidoformate. The latter type of compound is potentially explosive, andit is a considerable advantage of this invention that, in the adamantylseries, it is possible to use the virtually non-explosive, yet morereactive, chloroformate as a blocking group in peptide synthesis.

As is apparent from Reaction Sequences I and II, the

adamantyl chloroformates are useful as intermediates in variousreactions. It is also apparent from Reaction Sequence II that thecarbazates and azidoformates of adamantane, 3-methyladamantane,3,5-dimethyldamantane and homo-adamantane, are also useful as intermcdiates in the synthesis of the compounds of this invention. This inventionis further illustrated by the following specific examples:

EXAMPLE I l-hydroxyadamantane from I-bromoadamantane A reaction mixturecontaining 21 g. of l-bromoadarnantane, 50 ml. of 85% hydrazine hydrate,and 15-0 ml. of ethanol was heated to refluxing temperature for about 10hours. Removal of the volatile constituents by evaporation in vacuoyielded a solid residue comprising l-hydroxyadamantane. The residue wastreated with 100 ml. of cold water and the l-hydroxyadamantane taken upin 500 ml. of ether. The ether extract was separated and dried, and theether removed by evaporation in vacuo. The resulting residue weighing12.6 g. and melting at 220 C., was found to be identical in all respectsto l-hydroxyadamantane as prepared by Stetter, Ber., 92, 1679 (1959).

EXAMPLE II I-adamantyl chloroformate A solution containing 20 g. ofphosgene in 100 ml. of anhydrous benzene was maintained at about 20 C.by means of an ice-water bath. A mixture containing 8 g. ofl-hydroxyadamantane, 6 g. of pyridine, and 200ml. of ether was addeddropwise with stirring to the phosgene solution over a period of about 1hour while still maintaining the solution temperature at about 20 C.During the addition, a while solid precipitate was formed, and anadditional 100 ml. of anhydrous benzene were added to give a betterdispersion of the solids in the reaction mixture. After the addition hadbeen completed, the reaction mixture was maintained at ambienttemperature for about 1 hour and was then filtered. The filtrate waspoured over a mixture of ice and water, and this mixture was then placedin separatory funnel and shaken. The

organic layer was separated 'and dried, and its volume reduced by about80% by evaporation in vacuo. An aliquot of the resulting solution wasevaporated in vacuo to dryness at room temperature, yielding l-adamantylchloroformate as a while crystalline solid melting at about 40-42 C.Recrystallization was achieved from anhydrous petroleum-ether (boilingpoint=3060 C.) at -20 C., yielding crystals melting at about 4647 C.Infrared spectrum of the product confirmed the expected structure.

Analysis.Calc.: C, 61.54; H, 7.04; CI, 16.52. Found: C, 61.48; H, 7.06;CI, 16.93.

Adamantyl chloroformate can be stored essentially without decompositionat 4 C. in benzene-ether solution by addition of a small amount ofcalcium carbonate as a stabilizer.

EXAMPLE 1H 3,5-dimethyl-I-adamantyl chloroformate Following theprocedure of Example II, 3,5-dimethyll-hydroxyadamantane was reactedwith phosgene in benzene solution in the presence of pyridine. Thecompound was isolated and purified by the procedures of the same exampleand had the typical infrared absorption spectrum characteristic ofoxycarbonyl chlorides; M.P.=about 5-10 C.

EXAMPLE 1V 3-homo-adamantyl chloroformate 3-homo-adamantyl chloroformatewas prepared by the procedure of Example 11 from phosgene andS-hydroxyhomo-adamantane. This latter compound was prepared by theprocedure of Stetter and Goebel, Ben, 96, 550 (1963). The compound wasisolated in crystalline form from petroleum-ether at -50 C., but itsmelting point 6 was below 0 C. The liquid had the typical infraredabsorption spectrum characteristics of oxycarbonyl chlorides.

EXAMPLE V I-adamanyl carbamate l-adamantyl chloroformate was furthercharacterized by its conversion to the corresponding carbamate asfollows:

A solution of 75 mg. of l-adamantyl chloroformate in 25 ml. of anhydrousbenzene was saturated with gaseous ammonia for about 1 hour. Thereaction flask was then stoppered, and the resulting solution maintainedat ambient temperature for 24 hours. The reaction mixture was thenfiltered, and the filtrate shaken with 200 ml. of an ice-water mixture.Two hundred millimeters of ether were added, and the ether-benzene layerwas separated and dried. Evaporation of the resulting solution in vacuoyielded l-adamantyl carbamate, which melted at about 170-171 C. afterrecrystallization from boiling anhydrous ethanol.

Analysis.-Calc.: N, 7.25. Found, N, 6.83.

l-adamantyl carbamate prepared as above was found to be identical tol-ad'amantyl carbamate prepared by the interaction at elevatedtemperature of ammonia and adamantyl phenylcarbonate, prepared by thegeneral method of preparation of phenylcarbamates given by McLamore, J.Org. Chem., 20, 1379 (1955).

l-adamantyl N-methyl carbamate was prepared by the above procedure bysubstituting methylamine for ammonia. l-adamantyl N-methyl carbamatethus prepared melted at about 127-129 C. on recrystallization from anether-benzene solvent mixture.

Analysis.Calc.: C, 68.86; H, 9.15; N, 6.69. Found: C, 68.51; H, 9.04; N,6.77.

EXAMPLE VI I-adamantyl .N-adamantyl carbamate l-adamant-yl chloroformatewas also characterized by conversion to the N-adamantyl carbamate byreaction with 'adamantylamine as follows:

A solution containing 0.3 g. of l-adamantyl chloroformate dissolved in12.5 ml. of anhydrous ether was added to a stirred solution containing 1g. of adamantylamine in 25 ml. of anhydrous ether in dropwise fashion atroom temperature. After the addition had been completed, stirring wascontinued for an extra half hour. Adamantylamine hydrochloride, aby-product of the reaction forming l-adamantyl N-adamantyl carbamate,was removed by filtration. The filtrate was washed twice with 5-ml.portions of 1 N aqueous hydrochloric acid and twice with water to removethe excess adamantylamine. The filtrate was then dried and concentratedby heating at atmospheric pressure. Pentane was then added to the heatedsolution to the point of incipient precipitation, and the solution wascooled, yielding l-adamantyl N-admantyl carbamate, melting at about305-3 10 C.

Analysis.Calc.: C, 76.55; H, 9.48; N, 4.25. Found: C, 76.65; H, 9.68; N,4.09.

The adamantyl carbamates are useful as insecticides.

EXAMPLE VII 1 -adamantyl azidoformate Forty milligrams of sodium nitritecrystals were added to a mixture of mg. of l-adamantyl carbazate, 1 ml.of 2 N aqueous hydrochloric acid and 2 ml. of acetone. The mixture wasshaken until the crystals had dissolved. Two milliliters of water wereadded. A water-insoluble yellow oil was obtained and was extracted withthree 25- ml. portions of hexane. The hexane extracts were combined andwashed with 10% hydrochloric acid, 10% sodium bicarbonate solution, andWater. The hexane solution was then separated and dried. Evaporation ofthe hexane in vacuo yielded a pale yellow oily liquid which had thetypical infrared absorption spectrum of an acid azide.

If desired, the azidoformate can also be prepared utilizing otherstandard reagents, as for example, by the reaction of adamantylchloroformate and sodium azide.

EXAMPLE VIII I-adamantyl carbazate A solution containing 2 g. ofl-adamantyl chloroformate in 150 ml. of benzene was added slowly to awellstirred solution of 2.5 g. of anhydrous hydrazine in 20 ml. oft-butyl alcohol. After the reaction mixture had been stirred for abouttwo hours, the solvents were removed in vacuo. The sirupy residue wasdissolved in a mixture of 150 ml. of ether and 10 ml. of water. Theether layer was separated, Washed with 25 -ml. portions of water, with 5ml. of 1% sodium carbonate solutions, and again with 5 ml. of water. Theethereal solution was dried. Ten milliliters of anhydrous hexane wereadded and the solution concentrated to a volume of about ml. Cooling thesolution at about 10 C. yielded shiny, white crystalline plates ofl-adamantyl carbazate melting at about 141-142 C.

Analysis.-Calc.: N, 13.32. Found: N, 12.99.

l-adamantyl carbazate can also be prepared by the in teraction ofl-adamantyl p-nitrophenyl carbonate and hydrazine. l-adamantylp-nitrophenyl carbonate itself is prepared from l-hydroxyadamantane bythe method of Anderson and McGregor, J. Am. Chem. Soc., 79, 6181 (1964).The carbonate melts at about 106-108 C. on recrystallization from ahexane-ether solvent mixture.

Analysis.-Calc.: C, 64.34; H, 6.04; N, 4.41. Found: C, 64.16; H, 5.81;N, 4.60.

l-adamantyl carbazate can also be prepared by heating O-l-adamantylS-methyl thiolcarbonate with hydrazine. O-l-adamantyl S-methylthiolc'arbonate itself is prepared from l-hydroxyadamantane and methylchlorothiofor mate according to the general procedure described byCarpino, J. Org. Chem., 28, 1910 (1963).

3,5-dimethyl-1-adamantyl earbazate was prepared from3,5-dimethyl-l-adamantyl chloroformate and hydrazine according to theabove procedure. In addition, l-homoadamantyl carbazate was preparedfrom l-homo-adamantyl chloroformate and hydrazine. Both of the abovecompounds gave the typical infrared carbazate spectrum, having thestrong absorption at 5.9;. and 6.1a characteristic ofoxycarbonylhydrazides.

Following the above procedure, 3-homo-adamantyl chloroformate wasreacted with anhydrous hydrazine to yield the corresponding c'arbazatewhich melted at about 67 C.

A nalysis.Calc.: N, 12.41. Found: N, 11.97.

Following the above procedure, 3,5-dimethyl-1adamantyl chloroformate wasreacted with anhydrous hydrazine to yield the corresponding carbazatejM.P. =74 75 C.

Analysis.--Calc.: N, 11.76. Found: N, 11.37.

3-methyl-1-adam'antyl chloroformate and carbazate are prepared bysubstituting 3-methyl-1-adamantyl alcohol for the corresponding3,5-dimethyl compound employed in the above procedure.

EXAMPLE IX N-1 -adamanty loxycarbonyl-D-phenylglycine A solution ofsodium D-phenylglycine was prepared by suspending 151 mg. ofD-phenylglycine in a mixture of 2 ml. of water and 1.2 ml. of 1 Naqueous sodium hydroxide at 0 C. A second solution containing 225 mg. ofl-adamantyl chloroformate in a mixture of 2.5 ml. of dioxane and 1 ml.of ether was added in 5 portions to the sodium D-phenylglycinatesolution over a period of about 40 minutes. During the addition of theacid chloride solution an additional 1 m1. of 1 N aqueous sodiumhydroxide was added dropwise in order to maintain a slightly alkaline pHin the reaction mixture. The reaction mixture was next extracted withthree volumes of ether to remove any unreacted adamantyl chloroformate.The alkaline aqueous layer was cooled to about 0 C. and cautiouslyacidified with phosphoric acid until a pH of approximately 4.5 wasattained. A milky precipitate of N-1-adamantyloxycarbonyl-Dphenylglycine formed and was extracted with ether. The ether solutionwas sepa-. rated and dried. Evaporation of the ether in vacuo yielded anoily residue trituration of which with a few drops of cyclohexanefollowed by refrigeration at about 0 C. yieldedN-l-adamantyloxycarbonyl-D-phenylglycine as a white crystalline solidweighing 228 mg. and melting at about 119121 C.

Analysis.-Calc.: C, 69.28; H, 7.04; N, 4.25. Found: C, 69.22; H, 7.17;N, 4.18.

The above compound can also be prepared by the interaction ofl-adarnantyl azidoformate and phenylglycine in the presence oftri-ethylamine. Furthermore, the same derivative can be prepared byreaction of the amino acid with l-adamantyl p-nitrophenyl carbonate orwith 0-1- adamantyl S-rnethyl thiolcarbonate.

EXAMPLE X N-1 -adamantyl0xycarb0nyl glycine Following the procedure ofExample IX, l-adamantyl chloroformate was reacted with sodium glycinateto yield N-l-adamantyloxycarbonyl glycine melting at about 141- 142.5 C.after recrystallization from hexane.

Analysis.Ca1c.: N, 5.53, Found: N, 5.81.

In addition to the amino acids utilized in Examples IX and X, thefollowing amino acids will also yield adamantyloxycarbonyl derivatives:leucine, isoleucine, tyrosine, valine, serine, alanine, phenylalanine,DOPA, norleucine, histidine, di-iodo tyrosine, arginine, cysteine,methionine, ethionine, proline, hydroxyproline, aspartic acid andglutamic acid.

We claim:

1. An adamantyl carbazate of the formula wherein AD is 'a member of thegroup consisting of adamantyl, methyladamantyl, dimethyladamantyl andhomoadamantyl.

2. A compound according to claim 1, said compound being l-adamantylcarbazate.

3. A compound according to claim 1, said compound being3,5-dimethyl-l-adamantyl c'arbazate.

4. A compound according to claim 1, said compound being 3-homo-adamantylcarbazate.

References Cited UNITED STATES PATENTS 2,920,994 l/1960 Epperly 260-482XR LORRAINE A. WEINBERG-ER, Primary Examiner.

A. P. HALLUIN, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,369,041 February 13, 1968 Koert Gerzon et al.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, between lines 40 to 45, the portion of the formula reading:

R 0 II should read C C line 62, "turyl" should read furyl Column 5,lines 34 and 46, "while",

two occurrences, should read white Column 6, line 5, "adamanyl" shouldread adamantyl line 16, "millimeters should read milliliters Column 7,line 17, 25" should line 33, "benzene" should read hexane read 35 (SEAL)Signed and sealed this 17th day of March 1970. Attest:

WILLIAM E. SCHUYLER, JR.

Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer

